1. Field of the Invention
The present invention relates generally to the administration of certain antibiotics to animals, and in particular to antibiotics that induce oxidant stress, and are consequently dose-limited.
2. Description of the Prior Art
Numerous agents have been developed, tested and utilized in the treatment of various cancers by chemical means. Thus, a number of effective anti-cancer agents have been isolated which offer sufficient antineoplastic activity to warrant their use in cancer chemotherapy. A particularly effective family of agents belongs to the anthracycline group, and includes daunorubicin, doxorubicin, Chromomycin A, olivomycin, Rhodomycin A and Rhodomycin B. Another effective antineoplastic is the glycopeptide antibiotic, bleomycin.
While the above representative antibiotics have proven effective, they possess a serious limitation to their use, as there is an absolute, cumulative dose limitation to their administration that is believed to result from their participation in the generation of toxic levels of oxidants. For example, it has been found that amounts of doxorubicin and other anthracyclines administered beyond the dose-limiting level, causes cumulative damage to myocardial cells, that leads to serious and often lethal congestive cardiomyopathy. Regrettably, the maximum amount of these compounds that can be administered before cardiotoxicity results, is frequently inadequate to achieve even minor arrest of certain cancerous conditions. The mechanism of participation by the antibiotics of the anthracycline group in causing cardiotoxicity, is believed to be due to the reduction of the anthracycline and the subsequent reaction of the reduced form with oxygen to form toxic metabolites believed to be free radical species, all in quantities which exceed the capacity of the endogenous myocytic detoxification pathways.
In particular, doxorubicin causes the production of free radicals from NADPH (reduced nicotinamide adenine dinucleotide phosphate) and NADH (reduced nicotinamide adenine dinucleotide) present in microsomal systems, increases oxygen consumption of both hepatic microsomes and heart sarcosomes, and stimulates superoxide formation in cardiac submitochondrial particles, with the result that oxygen radical levels exceed the disposing capacity of the cells. See Handa, K., and S. Santo. "Generation of Free Radicals of Quinone Containing Anticancer Chemicals in NADPH-Microsome Systems as Evidenced by Initiation of Sulfite Oxidation," JAPAN S. CANCER RES. (Tokyo). 66:43-47 (1975); Bachur, N. R., Gordon, S. L., and M. V. Gee. "A General Mechanism for Microsomal Activation of Quinone Anticancer Agents to Free Radicals," CANCER RES. 38:43-47 (1978); Goodman, J., and P. Hochstein. "Generation of Free Radicals and Lipid Peroxidations by Redox Cycling of Andriamycin and Daunomycin," BIOPHYSICAL RES. COMMUNICATIONS. 77(#2) (1977); Thayer, W. S. "Andriamycin Stimulated Superoxide Formation in Submitochondrial Particles," CHEM.-BIOL. INTERACT. 19:265-278 (1977); Meyers, C. E., McGuire, W., and R. Young. "Andriamycin: Amelioration of Toxicity by Alpha Tocopherol," CANCER TREAT. REP. 60:961-926 (1976) and Doroshow, J. "Role of NADH Dehydrogenase in Oxygen Radical Formation by Anthracycline (a) Antibiotics," PROC. AM. ASSOC. CLIN. RES. 23:172 (1982).
In view of the above, various methods have been investigated and developed that attempt to prevent this antibiotic-induced free radical-mediated damage to normal tissues, however these techniques have all been of limited success in humans ("In International Symposium on Andriamycin", S. K. Carter, A. DiMarco, M. Ghione, et. al., editors, Springer-Verlag, New York. (1972)). Thus, Vitamin E has been used with some effect in certain species, but has failed to work at tolerable doses in humans (Krivit, W., "Adriamycin Cardiotoxicity Amelioration .alpha.-tocopherol", AM. J. PED. HEMATOL./ONCOL. 1(#2):151-153 (1979); and Wang, Y. M., Madanat, D. D., Kimball, T. C., Gleiser, C. A., Ali, M., Kaufman, W., and Vaneys, J., "Effect of Vitamin E Against Adriamycin Induced Toxicity in Rabbit", CANCER RES. 40:1022-27 (1980).
Co-enzymes Q.sub.9 and Q.sub.10 are of potential utility but have thus far offered no proven clinical benefit ("In The Biomedical and Clinical Aspects of Coenzyme Q, Vol. I", K. Folkers, and Y. Yamamura, editors, Elsevier Scientific Publishing Company, New York. (1977); "In The Biomedical and Clinical Aspects of Coenzyme Q, Vol. II", Y. Yamamura, K. Folkers, and Y. Ito, editors, Elsevier/North Holland Biomedical Press, New York. (1980); and "In The Biomedical and Clinical Aspects of Coenzyme Q, Vol. III", K. Folkers, and Y. Yamamura, editors, Elsevier/North-Holland Biomedical Press, New York (1981)).
Lastly, N-acetyl cysteine and other sulfhydryl group-donating compounds have shown mixed results, in that they have often protected the tumor cells as well as the normal host tissues from this antibiotic-induced damage (Doroshow, J., Locker, G. Y., Ifrim, I., and Myers, C. E., "Prevention of Doxorubicin Cardiac Toxicity in the Mouse by N-Acetylcysteine." J. CLINIC. INVEST. 68:1053-1064 (1981)).
The foregoing lack of conclusive efficacy, coupled with the apparent lack of discrimination (indicated with respect to the sulfhydryl group-donating compounds) suggests that a great need continues to exist for the development of a specific and efficacious method for the control of antibiotic-induced oxidant stress and consequent toxicity, with the concurrent benefit of the increased tolerance to the above discussed anti-cancer agents.